Combination therapy for effecting weight loss and treating obesity

ABSTRACT

The present invention features a novel therapy for effecting weight loss which involves treating a subject with a sympathomimetic agent (e.g., phentermine or a phentermine-like drug) in combination with an anticonvulsant sulfamate derivative (e.g., topiramate) such that the subject experiences weight loss. 
     The combination methods of the present invention also are effective against symptoms associated with Syndrome X. The invention also features pharmaceutical compositions and kits for use in the practice of these novel therapies.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/683,353, filed Jan. 6, 2010, which is a continuation of U.S. patentapplication Ser. No. 11/385,233, filed Mar. 20, 2006, which is acontinuation-in-part of U.S. patent application Ser. No. 10/454,368,filed Jun. 3, 2003, which is a continuation-in-part of U.S. patentapplication Ser. No. 09/593,555, filed Jun. 14, 2000, now abandoned,which claims priority under 35. U.S.C. §119(e)(1) to provisional U.S.Patent Applications Ser. No. 60/139,022, filed Jun. 14, 1999, Ser. No60/178,563, filed Jan. 26, 2000, and Ser. No. 60/181,265, filed Feb. 9,2000. The aforementioned patent applications are incorporated herein byreference in their entireties.

BACKGROUND OF THE INVENTION

About 97 million adults in the United States are overweight or obese.The medical problems caused by overweight and obesity can be serious andoften life-threatening, and include diabetes, shortness of breath,gallbladder disease, hypertension, elevated blood cholesterol levels,cancer, arthritis, other orthopedic problems, reflux esophagitis(heartburn), snoring, sleep apnea, menstrual irregularities, infertilityand heart trouble. Moreover, obesity and overweight substantiallyincrease the risk of morbidity from hypertension, dyslipidemia, type 2diabetes, coronary heart disease, stroke, gallbladder disease,osteoarthritis and endometrial, breast, prostate, and colon cancers.Higher body weights are also associated with increases in all-causemortality. Most or all of these problems are relieved or improved bypermanent significant weight loss. Longevity is likewise significantlyincreased by permanent significant weight loss.

Weight loss treatments vary depending, at least in part, on the degreeof weight loss one is attempting to achieve in a subject as well as onthe severity of overweight or obesity exhibited by the subject. Forexample, treatments such as low-fat diet and/or regular exercise areoften adequate in cases where a subject is only mildly overweight. Suchtreatments can be enhanced by controlled use of over-the-counterappetite suppressants including caffeine, ephedrine andphenylpropanolamine (Acutrim®, Dexatrim®). Moreover, prescriptionmedications including amphetamine, diethylpropion (Tenuate®), mazindol(Mazanor®, Sanorex®), phentermine (Fastin®, Ionamin®), phenmetrazine(Preludin®), phendimetrazine (Bontrol®, Plegine®, Adipost®, Dital®,Dyrexan®, Melfiat®, Prelu-2®, Rexigen Forte®), benzphetamine (Didrex®)and fluoxetine (Prozac®) are often used in the treatment of seriouslyoverweight and/or obese subjects or patients. However, such treatments,at best, result in only ˜5-10% weight loss (when accompanied with dietand exercise). Moreover, most of these treatments ultimately proveinadequate because they are either dangerous, ineffective or quicklylose their anorexient effect.

At least one class of these prescription medications, the phentermines(Fastin®, Ionatnin®), have been used as monotherapy in the treatment ofobesity for about 30 years. The phentermines are members of a class ofdrugs known as the sympathomimetics for their ability to mimicstimulation of the central nervous system. The phentennines act on thehypothalamus, an appetite control center of the brain. Phenterminemonotherapy can increase weight loss when used in combination with dietand exercise, as compared to diet and exercise alone. However, the drugloses effectiveness after about two weeks and, in fact, is not approvedby the FDA for use beyond six weeks. Moreover, weight loss may not bepermanent, especially after the drug is discontinued. Phenterminetreatment is also associated with side effects including nervousness,irritability, headache, sweating, dry-mouth, nausea, and constipation.

In general, available weight loss drugs have limited efficacy and someclinically significant side effects. Studies of the weight lossmedications dexfenfluramine (Guy-Grand, B. et al. (1989) Lancet2:1142-5), orlistal (Davidson, M. H. et al. (1999) JAMA 281:235-42),sibutrantine (Bray, G. A. et al. (1999) Obes. Res. 7:189-98), andphentermine (Douglas, A. et al. (1983) Int. J. Obes. 7:591-5) have shownsimilar effectiveness. Studies for each demonstrated a weight loss ofabout 5% of body weight for drug compared with placebo. Other seriousconsiderations limit the clinical use of these drugs. Dexfenfluraminewas withdrawn from the market because of suspected heart valvulopathy,orlistat is limited by GI side effects, sibutramine can causehypertension, and phentermine has limited efficacy.

Various combination therapies that include phentermine as one of theagents have been investigated and have met with mixed success. Thephentermines were, up until around 1997, often prescribed along withfenfluramine (Pondimin®) or dexfenfluramine (Redux®), nicknamed “fen”,as a combination therapy known as fen-phen. Fenfluramine is a potentreleaser of serotonin from serotonergic neurons which acts on a cerebralappetite center. When combined with phentermine, fenfluramine had theeffect of enhancing and extending the anorexient action of phentermine.However in 1997, the Food and Drug Administration (“FDA”) askedmanufacturers to withdraw Pondimin® and Redtux® due to studies whichstrongly suggested that the drugs cause damage to the mitral valve ofthe heart and pulmonary hypertension.

More recently, it has been suggested that phentermine in combinationwith anti depressants is a potentially effective therapy for effectingweight loss, U.S. Pat. No. 5,795,895. In particular, theanti-depressants suggested for use in this new combination therapy aremembers of a class of compounds known as selective serotonin reuptakeinhibitors (SSRIs) which include fluoxetine (Prozac®), sertraline(Zoloft®), fluvoxamine maleate (Luvox®) and trazodone hydrochloride(Desyrel®). The combination therapy is also suggested to treatcoexisting depression and/or obsessive-compulsive disorder.

Phentermine has also recently been tested in combination with bupropion(Wellbutrin®) for the treatment of obesity. Bupropion is anantidepressant that inhibits dopamine reuptake, as compared to serotoninuptake. It is also used to treat Attention Deficit Disorder (ADHD),bipolar depression, chronic fatigue syndrome, cocaine addiction,nicotine addiction, and lower back pain. While bupropion alone had amodest effect as a weight loss agent (when prescribed to patientsfollowing a 1200 calorie per day diet), patients receiving phenterminein combination with bupropion experienced no greater weight loss thanthose receiving bupropion alone. Moreover, bupropion use has beenassociated with drug-induced seizures causing it to be removed from themarket by the FDA for at least five years before its re-introduction in1989.

Accordingly, there exists a need for new, more effective weight losstreatments which are accompanied by fewer adverse or undesirable sideeffects or less serious side effects. In particular, there exists a needfor developing medical weight loss treatments which can potentiallylower major endpoints such as death and/or myocardial infarction ratesby directly treating obesity rather than treating the consequences ofobesity (e.g., diabetes, hypertension, hyperlipidernia), as is currentlythe practice.

SUMMARY OF THE INVENTION

The present invention features a novel therapy for effecting weight losswhich involves treating a subject with a sympathomimetic agent incombination with an anticonvulsant sulfamate derivative such that thesubject experiences weight loss. In one aspect, the sympathomimeticagent is a compound having anorectic activity (e.g., amphetamine,methamphetamine, benzphetamine, phentermine, chlorphenterinine,diethylpropran, phenmetrazine, and phendimetrazine). Preferably, thesympathomimetic agent is the drug phentermine (nicknamed “phen”). Inanother aspect, the anticonvulsant sulfamate derivative is the drugtopiramate,

The combination methods of the present invention also are effectiveagainst symptoms associated with Syndrome X. Accordingly, in anotheraspect the invention features methods for treating Syndrome X with acombination of a sympathomimetic agent and an anticonvulsant sulfamatederivative (e.g., phentermine and topiramate, respectively) such that atleast one symptom associated with Syndrome X is affected. Moreover, thecombination methods of the present invention have been shown to havebeneficial side effects, such as ameliorating sleep apnea and loweringblood pressure, blood glucose, blood lipid, and Hgb AlC levels.Accordingly, in another aspect the invention features methods fortreating at least one side effect associated with obesity. In apreferred embodiment, at least one side effect of obesity is treatedwith a combination of a sympathomimetic agent in combination with ananticonvulsant sulfamate derivative.

The invention also features pharmaceutical compositions includingtherapeutically effective amounts of a sympathomimetic agent incombination with an anticonvulsant sulfamate derivative. Kits includingthe pharmaceutical compositions of the present invention are alsofeatured (e.g., kits including the compositions packaged in a dailydosing regimen).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a novel combination therapy foreffecting weight loss in a subject. In particular, the present inventionprovides methods which involve treating the subject with atherapeutically effective amount of a combination of a sympathomimeticagent (e.g., phentermine or a phentermine-like compound) and ananticonvulsant sulfamate derivative (e.g., topiramate). The methods areparticularly useful for the treatment of overweight and/or obesity, aswell as in the treatment of Syndrome X.

The phrase “therapeutically effective amount” as used herein refers tothe amount of an agent, compound, drug, composition, or combination ofthe invention which is effective for producing some desired therapeuticeffect upon administration to a subject or patient (e.g., a humansubject or patient). The phrase “administering to a subject” or“administering to a patient” refers to the process of introducing anagent, compound, drug, composition or combination of the invention intothe subject or patient's body via an art-recognized means ofintroduction (e.g., orally, transdermally, via injection, etc.).

The term “sympathomimetic agent” is a term of art and refers to agentsor compounds which “mimic” or alter stimulation of the sympatheticnervous system (e.g., stimulates the peripheral nervous system) of anorganism (e.g., mimic the stimulation naturally effected by physicalactivity, psychological stress, generalized allergic reaction and othersituations in which the organism is provoked).

Preferred sympathomimetic agents for use in the present invention aswell as there general clinical uses or effects are set forth in Table 1.

TABLE I Sympathomimetic Agents and Clinical Uses Thereof

Main Clinical Uses Ring α Receptor β Receptor Agent Name substituent(s)R^(α) R^(β) R^(γ) A N P V B C CNS, 0 Phenylethylamine H H H Epinephrine3-OH, 4-OH OH H CH₃ A, P, V B, C Norepinephrine 3-OH, 4-OH OH H H PEpinine 3-OH, 4-OH H H CH₃ Dopamine 3-OH, 4-OH H H H P Dobutamine 3-OH,4-OH H H I* C Nordefrin 3-OH, 4-OH OH CH₃ H V Ethylnorepinephrine 3-OH,4-OH OH CH₂CH₃ H B Isoproterenol 3-OH, 4-OH OH H CH(CH₃)₂ B, CProtokylol 3-OH, 4-OH OH H 2* B Isoetharine 3-OH, 4-OH OH CH₂CH₃CH(CH₃)₂ B Metaproterenol 3-OH, 5-OH OH H CH(CH₃)₂ B Terbutaline 3-OH,5-OH OH H C(CH₃)₃ B Metaraminol 3-OH OH CH₃ H P Phenylephrine 3-OH OH HCH₃ N, P Tyramine 4-OH H H H Hydroxyamphetamine 4-OH H CH₃ H N, P CMethoxyphenamine 2-OCH₃ H CH₃ CH₃ B Methoxamine 2-OCH₃, 5-OCH₃ OH CH₃ HP Albuterol 3-CH₂OH, 4-OH OH H C(CH₃)₃ B Amphetamine H CH₃ H CNS, 0Methamphetamine H CH₃ CH₃ P CNS, 0 Benzphetamine H CH₃ —NHR^(γ) is 0replaced with 3* Ephedrine OH CH₃ CH₃ N, P B, C Phenylpropanolamine OHCH₃ H N Mephentermine H —CHR^(β)— is CH₃ N, P replaced with 4*Phentermine H ″ H 0 Chlorphentermine 4-Cl H ″ H 0 Fenfluramine 3-CF₃ HCH₃ C₂H₅ 0 Propylhexedrine 5*: phenyl ring H CH₃ CH₃ N is replaced withcyclohexyl Diethylpropion 6*: The substituent at the 1- 0 position isreplaced with 6, below. Phenmetrazine 7*: The substituent at the 1- 0position is replaced with 7, below. Phendimetrazine 8*: The substituentat the 1- 0 position is replaced with 8, below.

α Activity A = Allergic reactions (includes β action) N = Nasaldecongestion P = Pressor (may include β action) V = Other localvasoconstriction (e.g. in local anesthesia) β Activity B =Bronchodilator C = Cardiac CNS = Central nervous system 0 = Anorectic*Numbers bearing an asterisk refer to the substituents numbered in thebottom rows of the table; substituent 5 replaces the phenyl rings, and6, 7, and 8 are attached directly to the phenyl ring, replacing theethylamine side chain. ^(†)The α and β in the prototype formula refer tothe position of the C atoms in the ethylamine side chain.

In preferred embodiments, the sympathomimetic agent has anorexientproperties (e.g., suppresses appetite) or is anorectic withoutsignificant toxicity to a subject or patient (e.g., a human) attherapeutically effective doses. In a more preferred embodiment, thesympathomimetic agent has anorexient properties (e.g., suppressesappetite) or is anorectic without loss of efficacy or without adverse orundesirable side effects to a subject or patient (e.g., a human subjector patient) at therapeutically effective doses when prescribed incombination with topiramate. In yet another embodiment, thesympathomimetic agent is phentermine or a phentermine-like compound. Asdefined herein, a “phentermine-like compound” is a compound structurallyrelated to phentermine (e.g., an analog or derivative) which maintainsan anorectic activity similar to that of phentermine. A preferredphentermine-like compound is chlorphentermine. In yet anotherembodiment, the sympathomimetic agent is amphetamine or anamphetanaine-like compound. As used, herein, an “amphetamine-likecompound” is a compound structurally related to amphetamine (e.g., ananalog or derivative) which maintains an anorectic effect ofamphetamine. In yet another embodiment, the sympathomimetic agent isphenmetrazine or a phenmetrazine-like compound. As defined herein, a“phenmetrazine-like compound” is a compound structurally related tophenmetrazine (e.g., an analog or derivative) which maintains ananorectic effect of phenmetrazine. A preferred phenmetrazine-likecompound is phendimetrazine. Analogs and/or derivatives of the compoundsof the present invention can be tested for their ability to suppressappetite (e.g., suppress food intake) in a subject (e.g., a mammaliansubject).

In an exemplary preferred embodiment, the sympathomimetic agent isselected from the group consisting of amphetamine, methamphetamine,benzphetamine, phenylpropanolamine, phentermine, chlorphentermine,diethylpropion, phenmetrazine, and phendimetrazine (as set forth inTable 1. In a particularly preferred embodiment, the sympathomimeticagent is phentermine. It is also within the scope of the presentinvention to utilize other sympathomimetic agents including pseudoephedrine (a stereoisomer of ephedrine, SUDAFED®), methylphenidate(RITALIN®), tuaminoheptane, and other CNS stimulants including, forexample, caffeine.

The terms “anticonvulsant sulfamate derivative” and anticonvulsantsulfamate derivatives are terms of art and refer to a class ofsulfamate-derived compounds that possess anticonvulsant activity andhave an art-recognized use in the treatment of epilepsy. In particular,the anticonvulsant sulfamate derivatives are monosaccharide derivativeswith sulfamate functionality. The anticonvulsant sulfamate derivativesfor use in the present invention have one or more of the following modesof activity: modulation of voltage-dependent sodium conductance;potentiation of gamma-aminobutyric acid-evoked currents; inhibition ofthe kainate/alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid(AMPA) subtype of the glutamate receptor; and/or inhibition of carbonicanhydrase (e.g, a mechanism by which the anticonvulsant derivative ofthe present invention may decrease the sensation of taste). Theanticonvulsant sulfamate derivatives for use in the present inventionare described further in U.S. Pat. Nos. 4,513,006, 5,384,327, 5,498,629,5,753,693 and 5,753,694, as are methods of synthesizing suchanticonvulsant sulfamate derivatives. The aforementioned patents areincorporated by reference herein in their entireties.

In preferred embodiments, the anticonvulsant sulfamate derivative is acompound having the following formula (I):

wherein:

X is CH₂ or O;

R₁ is H or alkyl; and

R₂, R₃, R₄ and R₅ are independently H or lower alkyl, with the provisothat when X is O, then R₂ and R₃ and/or R₄ and R₅ together may be amethylenedioxy group of the following formula (II):

in which R₆ and R₇ are the same or different and are H or lower alkyl,or are joined to form a cyelopentyl or cyclohexyl ring.

R₁ in particular is hydrogen or alkyl of about 1 to 4 carbons, such asmethyl, ethyl, or isopropyl. Alkyl includes both straight and branchedchain alkyl. Alkyl groups R₂, R₃, R₄, R₅, R₆ and R₇ are about 1 to 3carbons and include methyl, ethyl, isopropyl and n-propyl.

A particular group of compounds of the formula (I) are those wherein Xis oxygen and both R₂ and R₃, and R₄ and R₅ together are methylenedioxygroups of the formula (II), wherein R₆ and R₇ are both hydrogen, bothalkyl, or combine to form a spiro cyclopentyl or cyclohexyl ring, inparticular, where R₆ and R₇ are both alkyl such as methyl. A secondgroup of compounds are those wherein X is CH₂ and R₄ and R₅ are joinedto form a benzene ring. A third group of compounds of the formula (I)are those wherein both R₂ and R₃ are hydrogen.

In preferred embodiments, the anticonvulsant sulfamate derivatives haveanorexient properties (e.g., suppress appetite) without significanttoxicity to a subject or patient (e.g., a human) at therapeuticallyeffective doses. In a more preferred embodiment, the anticonvulsantsulfamate derivatives have anorexient properties (e.g., suppressappetite) without significant adverse or undesirable side effects to asubject or patient (e.g., a human) at therapeutically effective doseswhen prescribed in combination with phentermine. In a particularlypreferred embodiment the anticonvulsant sulfamate derivative istopiramate (Topamax®). Topiramate, also referred to in the art as2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate, hasbeen demonstrated in clinical trials of human epilepsy to be effectiveas an adjunctive therapy or as monotherapy in treating simple andcomplex partial seizures and secondarily generalized seizures (E. Faughtet al. (1995) Epilepsia 36(suppl 4):33; S. Sachdeo et al. (1995)Epilepsia 36(suppl 4):33) and is currently marketed for the treatment ofsimple and complex partial seizure epilepsy with or without secondarygeneralized seizures.

Dosages, Administration and Pharmaceutical Compositions:

The choice of appropriate dosages for the drugs used in combinationtherapy according to the present invention can be determined andoptimized by the skilled artisan, e.g., by observation of the patient,including the patient's overall health, the response to the combinationtherapy, and the like. Optimization, for example, may be necessary if itis determined that a patient is not exhibiting the desired therapeuticeffect or conversely, if the patient is experiencing undesirable oradverse side effects that are too many in number or are of a troublesomeseverity.

Preferably, a sympathomimetic drug (e.g., a drug set forth in Table I)is prescribed at a dosage routinely used by the skilled artisan (e.g.,physician) to promote the desired therapeutic effect of the drug, whenthe drug is used as a monotherapy. Preferably, an anticonvulsantsulfamate derivative (e.g., a compound having formula I) is prescribedat a lower dosage than routinely used by the skilled artisan (e.g.,physician) to promote the desired therapeutic effect of the drug, whenthe drug is used as a monotherapy (e.g., in the treatment of epilepsy).In a preferred embodiment, a sympathomimetic drug or anticonvulsantsulfamate derivative is prescribed at a dose of between 5-1000preferably between 10-1500, more preferably between 20-1000 and mostpreferably between 25-50 mg daily.

It is especially advantageous to formulate compositions of the inventionin unit dosage form for ease of administration and uniformity of dosage.The term “unit dosage forms” as used herein refers to physicallydiscrete units suited as unitary dosages for the individuals to betreated. That is, the compositions are formulated into discrete dosageunits each containing a predetermined, “unit dosage” of an activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationsof the novel dosage unit forms of the invention are dependent on theunique characteristics of the composition containing the anticonvulsantor sympathomimetic agent and the particular therapeutic effect to beachieved. Dosages can further be determined by reference to the usualdose and manner of administration of the ingredients. It is also withinthe scope of the present invention to formulate a single physicallydiscrete dosage form having each of the active ingredients of thecombination treatment (e.g., a single dosage form having ananticonvulsant agent and a sympathomimetic agent).

The method of administration of compositions or combinations of theinvention will depend, in particular, on the type of sympathomimeticagent used and the chosen anticonvulsant sulfamate derivative. Thesympathomimetic agent and the anticonvulsant sulfamate derivative may beadministered together in the same composition or simultaneously orsequentially in two separate compositions. Also, one or moresympathomimetic agents or one or more anticonvulsant sulfamatederivatives may be administered to a subject or patient either in theform of a therapeutic composition or in combination, e.g., in the formof one or more separate compositions administered simultaneously orsequentially. The schedule of administration will be dependent on thetype of sympathomimetic agent(s) and anticonvulsant sulfamatederivative(s) chosen. For example, a sympathomimetic agent can have astimulant effect and the degree of such stimulant effect may varydepending on the sympathomimetic agent chosen. Accordingly, asympathomimetic agent having a significant stimulant effect might beadministered earlier in the day than administration of a sympathomimeticagent having a lesser stimulant effect. Likewise, an anticonvulsantsulfamate derivative can have a sedative effect and the degree of suchsedative effect may vary depending on the anticonvulsant sulfamatederivative chosen. Accordingly, an anticonvulsant sulfamate derivativehaving a significant sedative effect might be administered later in theday than administration of an anticonvulsant sulfamate derivative havinga lesser sedative effect. Moreover, sympathomimetic agents and/oranticonvulsant agents having lesser stimulant or sedative effects,respectively, may be administered simultaneously.

Sympathomimetic agents and/or anticonvulsant sulfamate derivatives canalso be administered along with a pharmaceutically acceptable carrier.As used herein “pharmaceutically acceptable carrier” includes anysolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, and the like. The useof such media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active compound, use thereof in compositions ofthe invention is contemplated.

A sympathomimetic agent alone, or in combination with an anticonvulsantsulfamate derivative in the form of a composition, is preferablyadministered orally. When the composition(s) are orally administered, aninert diluent or an assimilable edible carrier may be included. Thecomposition and other ingredients may also be enclosed in a hard or softshell gelatin capsule, compressed into tablets, or incorporated directlyinto the individual's diet. For oral therapeutic administration, thecomposition may be incorporated with excipients and used in the form ofingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like. The percentage of thecompositions and preparations may, of course, be varied. The amount ofactive compound in such therapeutically useful compositions is such thata suitable dosage will be obtained. In a particularly preferredembodiment, the present invention includes pharmaceutical compositioncomprising a therapeutically effective amount of a sympathomimetic agentand an anticonvulsant sulfamate derivative. In one embodiment, thepresent invention includes a therapeutically-effective amount of asympathomimetic agent and an anticonvulsant sulfamate derivativepackaged in a daily dosing regimen (e.g., packaged on cards, packagedwith dosing cards, packaged on blisters or blow-molded plastics, etc.).Such packaging promotes products and increases patient compliance withdrug regimens. Such packaging can also reduce patient confusion. Thepresent invention also features such kits further containinginstructions for use.

The tablets, troches, pills, capsules and the like may also contain abinder, an excipient, a lubricant, or a sweetening agent. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit. For instance, tablets, pills, or capsules maybe coated with shellac, sugar or both, or course, any material used inpreparing any dosage unit form should be pharmaceutically pure aridsubstantially non-toxic in the amounts employed.

A sympathomimetic agent, alone or in combination with an anticonvulsantsulfamate derivative, can also be administered in a convenient mannersuch as by injection (subcutaneous, intravenous, etc.), inhalation,transdermal application, or rectal administration. Depending on theroute of administration, the composition containing the sympathomimeticagent and/or anticonvulsant sulfamate derivative may be coated with amaterial to protect the compound from the action of acids and othernatural conditions which may inactivate the compounds or compositions.

To administer the compositions, for example, transdermally or byinjection, it may be necessary to coat the composition with, orco-administer the composition with, a material to prevent itsinactivation. For example, the composition may be administered to anindividual in an appropriate diluent or in an appropriate carrier suchas liposomes. Pharmaceutically acceptable diluents include saline andaqueous buffer solutions. Liposomes include water-in-oil-in-water CGFemulsions as well as conventional liposomes (Strejan et al. (1984) J.Neuroimmunol. 7:27). To administer the compositions containing thesympathomimetic agents and/or anticonvulsant sulfamate derivativesparenterally or intraperitoneally, dispersions can be prepared inglycerol, liquid polyethylene glycols, and mixtures thereof and oils.Under ordinary conditions of storage and use, these preparations maycontain a preservative to prevent the growth of microorganisms.

Compositions suitable for injectable use include sterile aqueoussolutions (where water soluble) or dispersions and sterile powders forthe extemporaneous preparation of sterile injectable solutions ordispersion. In all cases, the composition must be sterile and must befluid to the extent that easy syringability exists. It must be stableunder the conditions of manufacture and storage and must be preservedagainst the contaminating action of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyetheylene gloycol, and the like), suitablemixtures thereof, and vegetable oils. The proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case of dispersionand by the use of surfactants. Prevention of the action ofmicroorganisms can be achieved by various antibacterial and antifungalagents. In many cases, it will be preferable to include isotonic agents,for example, sugars, polyalcohols such as mannitol and sorbitol, orsodium chloride in the composition. Prolonged absorption of theinjectable compositions can be brought about by including in thecomposition an agent which delays absorption, for example, aluminummonostearate and gelatin.

A preferred aspect of the present invention features prescribingphentermine in combination with topiramate to effect weight loss and/orto treat Syndrome X and/or a subset of symptoms thereof. A preferreddose for phentermine is between about 5-60 mg daily, including but notlimited to doses of 8, 10, 15, 20, 25, 30, 35, 40, 45, 50 and 55 mgdaily. A particularly preferred dose for phentermine is about 15 mgdaily. In an exemplary embodiment the phentermine is of an immediaterelease form.

Preferably, the phentermine is taken by the patent in the morning andmore preferably, is taken before breakfast. The phentermine is besttaken in the morning because the drug is a stimulant as well as anappetite suppressant. When phentermine is prescribed (e.g., as part ofthe combination therapy described herein), physicians should be awareand may want to advise patients that the drug can be mildly habitforming. Phentermine can also cause increased nervousness, increasedenergy, irritability and, rarely, insomnia. Stopping phentermine mayalso cause tiredness lasting for up to 1-2 weeks. Phentermine can alsoraise blood pressure (e.g., during the early phases of treatment).

A preferred dose for topiramate is between about 50-1500 mg daily. Asdiscussed previously, prescription of topiramate at dosages of ≧400 mgdaily results is promotion of undesirable side effects (e.g., sedation,mental clouding). Accordingly, in a preferred embodiment, topiramate isprescribed at a dose of about 50-400 mg daily. In another preferredembodiment, the dosage of topiramate is increased gradually at theoutset of the therapy in order to reduce the chance of undesirable sideeffects associated with higher doses of the drug. In an exemplaryembodiment, the topiramate is administered at a dose of 25 mg daily forabout the first 5-7 days (e.g., 6 days) of treatment, at a dose of about50 mg daily for the next 5-7 days (e.g., 6 days), at a dose of 100 mgdaily for about the next 6-8 days (e.g., 7 days) and about 150 mg dailyfor the next 20-26 days. From this point forward, the topiramate can beadministered at a dose of 150-250 mg daily, including but not limited todoses of 175, 200, and 225 mg daily. A particularly preferred dose forcontinued therapy is about 200 mg of topiramate daily, in anotherexemplary embodiment, the topiramate is of an immediate release form. Inyet another exemplary embodiment, the topiramate is of a sustainedrelease form.

In a preferred embodiment, topiramate is taken later in the day than thephentermine. Preferably, the patient takes the topiramate just beforesupper or later in the evening. Topiramate is best given later in theday because the drug can be sedating. In other embodiments, thetopiramate is given BID (e.g., twice daily), TID (three times daily) orQID (four time daily). When prescribing topiramate, physicians should beaware and may warn to advise patients that the drug can cause tiredness,fatigue, dizziness, difficulty with speech or finding words, difficultyconcentrating, difficulty with balance, and/or numbness or tingling inthe hands or feet. Less common side effects are nausea, coordinationproblems, abdominal pain, slowed thinking nervousness, depression,breast pain, painful periods, double or blurred vision, palpitations,low white blood count and kidney stones. A physician should also advisepatients that the drug may not be taken if the patient is also takingDiamox (acetazolamide). No female patient should become pregnant whiletaking this drug as it may cause birth defects. If a female patientmisses a period she should immediately discontinue taking the medicationand inform the physician. Female patients should not be treatedaccording to the methods of the present invention if breast feeding achild. Patients should not drink alcohol or take sedating medicationswhile taking topiramate since excess sedation can occur. Patients shouldalso refrain from performing dangerous tasks (e.g. operating heavymachinery or driving) until they are comfortable with the side effectsof the full dose (e.g., 200-400 mg daily). Patients should be advisednot to increase the dosage beyond what is prescribed. Topiramate is nothabit forming.

Yet another embodiment of the present invention features pharmaceuticalcompositions (e.g., for oral administration) comprising phentermine andtopiramate in a single pharmaceutical formulation. Such compositions maybe preferred, for example, to increase patient compliance (e.g., byreducing the number of administrations necessary to achieve the desiredpharmacologic effect).

In a preferred embodiment, the pharmaceutical composition includesphentermine in an immediate release form and further includes topiramatein a controlled release formulation. As defined herein, an “immediaterelease formulation” is one which has been formulated to allow, forexample, the phentermine, to act as quickly as possible. Preferredimmediate release formulations include, but are not limited to, readilydissolvable formulations. As defined herein, a “controlled releaseformulation” includes a pharmaceutical formulation that has been adaptedsuch that drug release rates and drug release profiles can be matched tophysiological and chronotherapeutic requirements or, alternatively, hasbeen formulated to effect release of a drug at a programmed rate.Preferred controlled release formulations include, hut are not limitedto, granules, delayed release granules, hydrogels (e.g., of synthetic ornatural origin), other gelling agents (e.g., gel-forming dietaryfibers), matrix-based formulations (e.g., formulations comprising apolymeric material having at least one active ingredient dispersedtherethrough), granules within a matrix, polymeric mixtures, granularmasses, and the like.

In one embodiment, a controlled release formulation is a delayed releaseform. As defined herein, a “delayed release form” is formulated in sucha way as to delay, for example, topiramate's action for an extendedperiod of time. A delayed release form can be formulated in such a wayas to delay the release of an effective dose of topiramate for 4, 8, 12.16 or 24 hours following the release of phentermine. In yet anotherpreferred embodiment, a controlled release formulation is a sustainedrelease form. As defined herein, a “sustained release form” isformulated in such a way as to sustain, for example, the topiramate'saction over an extended period of time. A sustained release form can beformulated in such a way as to provide an effective dose of topiramate(e.g., provide a physiologically effective blood level) over a 4, 8, 12,16 or 24 hour period.

Preferred compositions include a tablet core consisting essentially oftopiramate, said core being in association with a layer of phentermine.Preferably, the core has a delayed or sustained dissolution rate. In anexemplary embodiment, a tablet can comprise a first layer containing,for example, phentermine (e.g., in an immediate release formulation) anda core containing, for example, topiramate in a delayed release orsustained release formulation. Other exemplary embodiments can include,for example, a barrier between the first layer and core, said layerserving the purpose of limiting drug release from the surface of thecore. Preferred harriers prevent dissolution of the core when thepharmaceutical formulation is first exposed to gastric fluid. Forexample, a barrier can comprise a disintegrant, a dissolution-retardingcoating (e.g., a polymeric material, for example, an enteric polymer),or a hydrophobic coating or film, and can be selectively soluble ineither the stomach or intestinal fluids. Such barriers permit thetopiramate to leach out slowly and can cover substantially the wholesurface of the core.

The above-described pharmaceutical compositions are designed to releasethe two effective agents of the combination therapy of the presentinvention sequentially, i.e., releasing topiramate after releasingphentermine, both agents being contained in the same pharmaceuticalcomposition. Preferred amounts of phentermine and topiramate are asdescribed above with particularly preferred compositions comprising fromabout 5 mg to about 60 mg phentermine and from about 50 mg to 1500 mgtopiramate. Particularly preferred compositions include at least 15 mgphentermine and at least about 50 mg, 100 mg or 200 mg topiramate.

Pharmaceutical compositions so formulated may contain additionaladditives, suspending agents, diluents, binders or adjuvants,disintegrants, lubricants, glidants, stabilizers, coloring agents,flavors, etc. These are conventional materials which may be incorporatedin conventional amounts.

In one embodiment, a method of the present invention is carried out,practiced or performed such that weight loss in the subject or patientoccurs. Accordingly, the methods of the present invention areparticularly useful for the treatment of overweight or obese patients.As defined herein, “overweight” subjects or patients are between about 1and 20 percent overweight (e.g., weighs 1-20% in excess of their idealbody weight). Also as defined herein, an “obese” subject or patient isgreater than 20 percent overweight (e.g., weighs >20% in excess of hisor her ideal body weight). Alternatively, the methods of the presentinvention are useful in the treatment of subjects or patients in need oflosing weight, but who are not necessarily overweight or obese. Forexample, it may be desirable to achieve weight loss in subjects orpatients having arthritis or prostheses such that the individualexperiences less adverse effects resulting from bearing weight.

The combination therapies of the present invention will generally beadministered until the patient has experienced the desired weight loss,and preferably has achieved an ideal body weight. Alternatively, thecombination therapies of the present invention can be administered untilthe patient has achieved a weight loss of 5-10%, 10-15%, 15-20% or20-25% of their initial body mass (e.g., the patient's starting weight).

The present inventor has also recognized that the combination therapy ofthe present invention ameliorates symptoms associated with Syndrome X.Syndrome X consists of a complex of medical problems that are largelyassociated with obesity, including, hypertension, diabetes or glucoseintolerance and insulin resistance, hyperlipidemia, and often tirednessand sleepiness associated with sleep apnea. Patients are often treatedwith combinations of antihypertensives, lipid lowering agents, insulinor oral diabetic drugs, and various mechanical and surgical treatmentsof sleep apnea. However, such treatments are often costly and do nottreat the underlying problem of obesity. Moreover, some of thetreatments for diabetes, including insulin and oral diabetic agents,actually aggravate Syndrome X by increasing insulin levels, increasingappetite, and increasing weight. This can lead to higher blood pressureand even higher cholesterol. Accordingly, one aspect of the presentinvention features a method of treating Syndrome X using the combinationtherapies described herein. In one embodiment, the invention features amethod of treating Syndrome X in a subject or patient which includestreating the subject with a therapeutically effective amount of acombination of an anticonvulsant sulfamate derivative (e.g., topiramate)and a sympathomimetic agent (e.g., phentermine or a phentermine-likecompound), such that at least one symptom associated with Syndrome X isaffected. As defined herein, “affecting a symptom” (e.g., affecting asymptom associated with Syndrome X) refers to lessening, decreasing theseverity of the symptom or reversing, ameliorating, or improving thesymptom (e.g., decreasing hypertension, ameliorating diabetes, reversingglucose intolerance or insulin resistance, lessening hyperlipidetnia, ordecreasing tiredness and sleepiness associated with sleep apnea).

Treatment of Syndrome X according to the methods of the presentinvention includes affecting at least one, preferably two, morepreferably three, more preferably four, five or six symptoms associatedwith Syndrome X. In a particularly preferred embodiment, all symptomsassociated with Syndrome X are affected (e.g., lessened, reversed,ameliorated, etc.)

The present inventor has also recognized that the combination therapy ofthe present invention ameliorates some side effects associated withobesity, as described herein. Accordingly, one aspect of the presentinvention features a method of treating at least one side effectassociated with obesity using the combination therapies describedherein. In one embodiment, the invention features a method of treatingat least one obesity-related side effect in a subject or patient whichincludes treating the subject with a therapeutically effective amount ofa combination of an anticonvulsant sulfamate derivative (e.g.,topiramate) and a sympathomimetic agent (e.g., phentermine or aphentermine-like compound), such that at least one obesity-related sideeffect is effected. As defined herein, a “side effect associated withobesity” includes a symptom or disorder in a subject (e.g., a patient)which is secondary and/or results from (e.g., directly and/or indirectlyresults from) a medical condition for which the subject is obese and/orbeing treated. In a preferred embodiment, the subject is obese and/or isbeing treated for obesity. In another embodiment, the subject has atleast one or more (e.g., two, three, four, five or more) side effect(s)selected from the group consisting of sleep apnea, high blood pressureand high blood sugar, high blood lipid, high Hgb AlC or otherart-recognized side effects associated with obesity,

Whether in the treatment of Syndrome X or in the practicing of themethods of the present invention to effect weight loss (e.g., in thetreatment of overweight and/or obesity) or in treatment of side effectsassociated with obesity, it will be apparent to the skilled artisan(e.g., physician) that monitoring of the patient is needed to determinethe effectiveness of the treatments and to potentially modify thetreatments (e.g., modify the dosing, time of drug administration,sequence of drug administration, us defined herein). Accordingly, incertain embodiments, the patient is monitored about every 2-6,preferably every 3-5 and more preferably every 4 weeks. Monitoring theeffective of treatment to achieve weight loss includes, but is notlimited to monitoring the subject or patient's body weight (e.g.,comparing the patient's initial body weight to that at a follow-upvisit, for example, four weeks after the initiation of treatment).Additional features of the subject or patient's health can also bemonitored (i.e., monitoring the patient's overall health and/ormonitoring the effectiveness of treatment of an undesired side effect ofobesity) including, but not limited to the patient's blood pressure,blood sugar, serum lipid levels, etc. Likewise, monitoring a subject orpatient for treatment of Syndrome X can include monitoring of at leastone, preferably more than one symptom associated with Syndrome X.

This invention is further illustrated by the following examples whichshould not be construed as limiting. The contents of all references,patents and published patent applications cited throughout thisapplication are hereby incorporated by reference.

EXAMPLE 1

Patients as part of the following trial were treated according to thefollowing dosage regimen. Patients took phentermine at a dose of 15 mgdaily throughout the weight loss program, before breakfast. For thefirst 6 days, patients took one 25 mg tablet of topiramate beforesupper. For the next 6 days, patients took two 25 mg tablets oftopiramate before supper. For the next 7 days (days 13-19), patientstook 100 mg before supper daily using 4-25 mg tablets of topiramatedaily. For days 20-26, patients took 150 mg of topiramate dailyconsisting of one-half of a 200 mg tablet and two 25-mg mg tablets oftopiramate. From that point on, unless instructed otherwise by thephysician, patients continued to take one 200 mg topiramate tablet dailybefore supper and continued the 15 mg phentermine daily in the morning.Patients were advised to drink at least eight (8) full glasses of waterdaily to reduce the risk of kidney stones which may result from takingtopiramate.

Patients were advised that while the effect of phentermine is fairlyrapid, the effect of topiramate is slower in onset. The weight reductioneffect of topiramate will continue for as long as 18 months on themedication. That is, the patient can expect to continue gradual weightloss for up to 18 months on the medication. Of course, weight loss ismaximal if the patient follows diet and/or exercise programs. The weightloss should exceed 15% of the patients starting weight. Thus, if thepatient weighs about 200 pounds as of the start date, he/she mightexpect to lose at least 30 pounds in a period of 12-18 months. Thefollowing patient data has been collected.

TABLE II Start Follow-Up Follow- Patient's Start Weight Blood Follow-Weight % Weight Up Blood Initials Age Sex (lbs) Pressure Up Date (lbs)Loss Pressure M. O.¹ 48 F 182 115/70 5 weeks 177 2.7% 120/80 9 weeks 1763.3% 110/70 T. M. 37 F 190 122/84 2 weeks, 178 6.3% 110/80 5 days 6weeks, 168 11.6% 125/80 2 days D. M.(A) 28 M 286 138/90 4 weeks 279 2.4%128/86 P. L. 55 F 144 132/84 4 weeks 141 2.1% 138/85 9 weeks 137 4.9%122/82 E. K. 52 F 181  130/100 5 weeks 175 3.3% 140/88 I. F. 41 F 196 95/60 6 weeks, 5 days D. M.(B)² 56 M 295 150/80 4 weeks, 297 (+0.7%)148/82 2 days 8 weeks, 287 2.7% 140/70 2 days ¹Patient M. O, was beingtreated with Meridia ® at the onset of the study, which continuedthrough the first 5 weeks of the study. At the 5-week-follow up, M. O.was switched to the phentermine/topiramate regime described above.²Patient D. M.(B) was being treated with phentermine alone at the onsetof the study and was taking the full dose of topiramate by the fourthweek of the study.

As is apparent from the above-described data, patients not previouslytreated with an anorexient at the outset of the study experienced anaverage of about 3.5% weight loss after only 2-6 weeks (e.g., patientT.M. lost 6.3% body weight, patient D.M.(A) lost 2.4% body weight,patient P.L. lost 2.1% body weight and patient E.K. lost 3.3% bodyweight). After only 6-9 weeks of treatment, patients (not previouslytreated with an anorexient at the outset of the study experienced anaverage of about 8.3% weight loss (e.g., patient T.M. lost 11.6% bodyweight and patient P.L. lost 4.9% body weight). The patient previouslyon Meridia® (patient M.O.) lost 3.3% body weight after being enrolled inthe program for 9 weeks. Moreover, the patient previously on phentermine(patient D.M.(B)) lost a total of 2.7% body weight after being enrolledin the program for about 8 weeks. This particular patient reported thatthis is the most significant weight loss he has achieved to date, thepatient having previously tried other conventional therapies.

In addition to the weight loss reported above, almost all patientsenrolled in the study experienced decreased blood pressure. Moreover,patients involved in the study who had previously taken Redux, phen-fen,Meridia and/or other weight loss treatments report that they have notpreviously experienced the benefits of the combinedphentermine/topiramate therapy. Patients report that they have noappetite, can resist food easily, can concentrate and function at work(even in attention-intensive jobs such as computer programming), havemore energy and feel better. Patients also report experiencing fewerside effects than any previous weight loss treatments tried.

EXAMPLE 2

Extended results of the trial described in Example 1.

A total of thirteen patients were treated for 1-9 months withphentermine (15 mg daily) in the morning and up to 400 mg, of topiramate(median dose 200 mg), in the evening. [Note: Patient D.M.(B) discussedabove is not included in this data as he was on phentermine treatmentprior to treatment with the combination therapy of the presentinvention.] Topiramate dose was gradually increased from 25 mg per dayin increments of 25-50 mg weekly until either desirable weight loss tookplace or until side effects limited dose increases. [Note: A fourteenthpatient discontinued treatment after 3 days due to nausea.] All thirteenpatients tolerated treatment well with minimal side effects. Along withtaking medication, patients were instructed to walk at least 30 minutesthree times per week and to follow a low fat diet. No patients had takendiet medication for at least 3 months prior to treatment. Averagebaseline BMI was 32.5 (range 26-48).

Average weight loss for the thirteen patients was 11.8%. For sevenpatients who were on treatment the longest (range 5-9 months), theaverage weight loss was 14.4%. Patients reported that they had little orno appetite and that they actually felt better (Topiramate's usefulnessis also being investigated as a mood stabilizer) than before therapy.Blood pressure, lipid, glucose, and Hgb AlC values were also favorablyaffected by this treatment.

Table III sets forth patient data for the thirteen above-describedpatients treated with the combination therapy of the present invention.

TABLE III Patient Data: Combination Therapy* % of Patient WeightBaseline Current Weeks on Current No. Loss BMI BMI Rx Status 1 7.7 38 3510 on Rx 2 10.3 25 23 4 Finished 3 6.8 48 44 5 d/c early-dropped out 416.8 30 24 35 on taper 5 23.2 30 23 41 on taper 6 8 41 38 40 on Rx 7 9.728 25 33 on taper 8 14.4 30 26 44 on Rx 9 15.9 27 21 32 on taper 10 9 3331 7 d/c early-will restart 11 12.9 28 24 22 Finished 12 7 29 27 5 on Rx13 12.1 34 31 6 on Rx *data for thirteen patients Average weight loss =11.8% (13 patients) Average weight loss ≧ 22 weeks on Rx = 14.4% (7patients) Average baseline BMI = 32.4

Table IV sets forth for the average blood pressure, blood glucose, HgbAlC and blood lipid value for the thirteen patients.

TABLE IV BP GLUCOSE HGBA1C CHOL TRIG mmHg mg/dL %* mg/dL mg/dL AveragePre- 131.3/ 107 6.48 212 189 Treatment Value  85.9 Average On 122.6/ 1025.05 210 172 Treatment Value  78.4 *Numbers include 1 diabetic patientwhose oral hypoglycemic was reduced by 50% while on the weight losstreatment.

One of the thirteen patients in the study also had severe sleep apneawith the usual complications of daytime sleepiness and fatigue. Hissymptoms have disappeared with the weight loss treatment.

Of the six patients (i.e., finished or on taper) who have completed thecombination therapy of the present invention, five of the six achieved abody mass index (EMI) of 24 or better. The average pre-treatment orbaseline BMI for these six patients was 28. The final average BMI was23.3. The average weight loss was 17%.

EXAMPLE 3

The 56-year old male patient described previously (D.M.(B)) who wasinitially taking phentermine alone and had topiramate added to hisregimen had a good effect from the combination. He once weighed as muchas 395 pounds. When Redux was still on the mark in the United States, hewas treated with a combination of diet, exercise, Redux and phentermine,His lowest weight attained was 285 pounds. When Redux was withdrawn fromthe market, he remained on phentermine but gained weight back to 295-300pounds. When topiramate was added to his regimen, he managed to lose 25pounds and is currently at 271 pounds, his lowest weight since he was inhis 20s. He, along with most of the patients treated so far, reportedthat the treatment with topiramate and phentermine had fewer sideeffects and was more effective than any previous weight loss treatmentusing medications that he and others had tried. This 56-year old manexhibited lowered blood pressure (approx. 15 mm Hg systolic and 10 mm Hgdiastolic).

EXAMPLE 4

Extended results of the trial described in Examples 1 and 2.

The cumulative data from a total of seventeen patients treated with thecombination weight loss treatment of the present invention are set forthin Table V.

TABLE V Patient Data: Combination Therapy* % BASE- WEIGHT LINE CURRENTWEEKS CURRENT PATIENT LOSS BMI BMI ON Rx STATUS 1 7.7 38 35 33 on Rx 210.3 25 23 4 Finished 3 6.8 48 44 5 d/c early- dropped out 4 16.8 30 2458 on taper 5 23.2 30 23 64 on taper 6 17.5 41 33 63 on Rx 7 9.7 28 2556 on taper 8 18.6 30 24 67 on Rx 9 15.9 27 21 55 on taper 10 9 33 31 7d/c early- will restart 11 12.9 28 24 22 Finished 12 7 29 27 5 d/cearly- will restart 13 12.1 34 31 6 d/c early- will restart 14 22.5 4632 16 on Rx 15 10.1 50 45 12 on Rx 16 6.4 27 24 4 Finished 17 6.3 27 256 on Rx *data for seventeen patients AVERAGE WEIGHT LOSS = 12.5% (7patients) AVERAGE WEIGHT LOSS ≧ 22 WEEKS ON Rx = 15.3% (8 patients)AVERAGE BASELINE BMI = 33.6

The present invention provides a novel combination therapy for thetreatment of obese or overweight patients that can result in weightlosses of greater than 5-10%, perhaps even as great as 15-20%. Thetherapy combines phentermine or a phentermine-like drug with drugpreviously recognized for the treatment of epileptic seizures, known astopiramate. The combination therapy results in greater initial weightloss than other recognized therapies, potential greater overall weightloss and can be continued for significant periods of time with fewer andless serious side effects than other recognized weight loss treatments.In particular, the combination therapy far surpasses the modestanorexient effects of phentermine monotherapy and can be continued forsignificant periods of time without the loss of effectivenessexperienced by patients being treated with phentermine alone. Moreover,the combination therapy has been found to ameliorate symptoms associatedwith Syndrome X and accordingly, has potential use in the treatment ofSyndrome X.

Equivalents:

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

What is claimed:
 1. A pharmaceutical composition formulated for oraladministration comprising 25 mg to 100 mg of topiramate, formulated forcontrolled release, and 5 mg to 15 mg of phentermine, formulated forimmediate release.
 2. A pharmaceutical composition formulated for oraladministration comprising 25 mg to 50 mg of topiramate, formulated forcontrolled release, and 5 mg to 8 mg of phentermine, formulated forimmediate release.
 3. A method of effecting weight loss in a subject inneed thereof by administering a pharmaceutical composition formulatedfor oral administration comprising 25 mg to 100 mg of topiramate,formulated for controlled release, and 5 mg to 15 mg of phentermine,formulated for immediate release.
 4. A method of effecting weight lossin a subject in need thereof by administering a pharmaceuticalcomposition formulated for oral administration comprising 25 mg to 50 mgof topiramate, formulated for controlled release, and 5 mg to 8 mg ofphentermine, formulated for immediate release.
 5. The pharmaceuticalcomposition of claim 1 or 2, wherein the composition further comprises apharmaceutically acceptable carrier,
 6. The pharmaceutical compositionof claim 1 or 2, wherein formulated for controlled release is formulatedfor delayed release.
 7. The pharmaceutical composition of claim 6,wherein delayed release is delaying the release of topiramate for atleast 4 hours following the release of phentermine.
 8. Thepharmaceutical composition of claim 1 or 2, wherein formulated forcontrolled release is formulated for sustained release.
 9. Thepharmaceutical composition of claim 8, wherein sustained release isproviding topiramate over at least a 4 hour time period.
 10. Thepharmaceutical composition of claim 1 or 2, wherein the composition is atablet, capsule, pill, troche, elixir, suspension, syrup or wafer. 11.The pharmaceutical composition of claim 10, wherein the tablet, capsuleor pill comprises a topiramate core in associate with a layer ofphentermine.
 12. The pharmaceutical composition of claim 10, wherein thetablet, capsule or pill comprises at least a first layer comprisingphentermine and at least a second layer comprising topiramate.
 13. Thepharmaceutical composition of claim 12, wherein the at least first layeris the outer most layer of the tablet, capsule or pill.
 14. Thepharmaceutical composition of claim 12, wherein the at least secondlayer is the core of the tablet, capsule or pill.
 15. The method ofclaim 3 or 4, wherein the composition is administered for 5 to 9 months.16. The method of claim 3 or 4, wherein the composition is administeredfor 12 to 18 months.
 17. The method of claim 3 or 4, wherein thecomposition is administered for up to 18 months.
 18. The method of claim3 or 4, wherein the composition is administered until the subject hasachieved a weight loss of at least 5% compared to the subject's weightprior to administration of the composition.
 19. The method of claim 18,wherein the composition is administered until the subject has achieved aweight loss of 5-10%,
 20. The method of claim 3 or 4, wherein thecomposition is administered until the subject has achieved a weight lossof at least 10% compared to the subject's weight prior to administrationof the composition.
 21. The method of claim 20, wherein the compositionis administered until the subject has achieved a weight loss of at10-15%.
 22. The method of claim 20, wherein the composition isadministered until the subject has achieved a weight loss of 15-20%. 23.The method of claim 20, wherein the composition is administered untilthe subject has achieved a weight loss of at 20-25%.